Update on Triple Negative Breast Cancer
George W. Sledge, Jr. MD
Stanford University
The Breast Cancer Layer Cake
All Breast Cancer
ER+
HER2+
Basaloid
Important subsets of breast cancers
defined by molecular markers and
by clinical treatment options
Basal (Triple-Negative)
Breast Cancer
– ER, PR, and HER2-negative
(“triple negative”)
– High nuclear grade and proliferative
indices
– BRCA-1 Positive
– Ethnic component
– Chemosensitive but poor prognosis
– Differential chemosensitivity?
The growing impact of Triple-Negative/Basal-like Breast Cancers
= TNBC in PubMed
= TNBC Clinical Trial in ClinicalTrials.gov (103 open)
= Basal and Breast in PubMed
• Inherited mutation
• 1/500 to 1/1000 in general population
• 1/50 in Jewish populations
• Mutation affects DNA damage repair
• Responsible for 1-2% of breast cancers
• Lifetime breast cancer risk 50 – 85%
• More aggressive tumors at younger ages
• Increases other cancer risks (ovarian)
Saslow et al. CA 2007
Rad50
BARD1 BRCA2
Nbs Mre11
Rad51 p53
Family History: Testing Considerations
• Know BRCA mutations
• Multiple close relatives with breast or ovarian cancer
• Breast cancer before the age of 50
• Both breast and ovarian cancer
• Bilateral breast cancer
• Close relatives with multiple cancers
• Male breast cancer
Saslow et al. CA 2007
Prophylactic Mastectomy
• Decreases breast cancer risk by 95%
• Consider only after significant counseling
• ASSO guidelines: – BRCA or other genetic mutations
– Strong family history
– ADH, ALH, LCIS on biopsy
– Difficult surveillance such as excessively dense breasts
Afonso JABFM 2009
Salpingo-oophorectomy
• Considered in known BRCA 1 or 2
• 80-95% reduction in ovarian cancer
• 50% reduction in breast cancer
• Negative effects
– Menopausal symptoms
– Increase cardiovascular risk
– Accelerated bone loss
– Decreased quality of life measures
Afonso JABFM 2009
Screening Tools
• Mammography
• Breast self-examination
• Clinical breast examination
• Digital mammography
• US
• MRI
Carolina Breast Cancer Study (CBCS)
Population-based case-control study
40% African-American / 60% Caucasian
50% under the age of 50 at diagnosis
1424 cases with IHC for ER, PR, HER2, CK5/6, HER1,
pathology data, TP53 and BRCA1 mutation data
Epidemiology of basal-like breast cancer,
Millikan et al.,
Breast Cancer Research and Treatment, 2008 (PMID 17578664)
Breast cancer
subtype
African-
American
Premenopausal
N (%)
African-
American
Postmenopaus
al N (%)
Caucasian
Premenopausal
N (%)
Caucasian
Postmenopaus
al N (%)
Luminal A
N = 796 108 (41.4%) 179 (56.3%) 216 (57.4%) 293 (66.5%)
Basal-like
N = 225 70 (27.2%) 52 (16.0%) 54 (14.5 %) 49 (9.3%)
HER2+/ER-
N = 116 22 (8.4%) 26 (7.7%) 24 (5.6%) 44 (6.0%)
Luminal B
N = 137 19 (7.3%) 26 (8.7%) 46 (12.4%) 46 (10.7%)
Unclassified
N = 150 41 (15.7%) 38 (11.3%) 38 (10.1%) 33 (7.5%)
Total: 1424
P < 0.0001 260 (100%) 321 (100%) 378 (100%) 465 (100%)
Distribution of breast cancer subtypes according to race and menopausal status using 1424
cases: invasive (1000) and in-situ (424) breast cancers
Luminal A
N=796
Basal-like
N=225
Menarche < 13 1.1 (0.9-1.3) 1.4 (1.1-1.9)
> 3 children 0.7 (0.5-0.9) 1.9 (1.1-3.3)
First birth < 26 0.7 (0.5-0.9) 1.9 (1.2-3.2)
Breastfeeding > 4m 0.9 (0.7-1.1) 0.7 (0.4-0.9)
Parity > 3 and
No breastfeeding 0.7 (0.5-0.9) 1.9 (1.1-3.3)
Waist:Hip > 0.84 1.5 (1.1-1.9) 2.3 (1.4-3.6)
Adjusted ORs
(95% CI)
N = 1424 cases
and
2022 controls
ROBERT
MILLIKAN
1958-2012
Epidemiology of basal-like breast cancer,
Millikan et al.,
Breast Cancer Research and Treatment, 2008 (PMID 17578664)
Triple-Negative Breast Cancer
Standard of Care: CTCTCT
Major Questions: 1.Which chemotherapy? 2.How long? 3.Combination or sequential?
New Drugs for Breast Cancer
1990s: • AIs (metastatic) • Goserelin • Zoledronate • Taxanes (metastatic) • Epirubicin (adjuvant) • Vinorelbine • Gemcitabine • Liposomal doxorubicin • Capecitabine • Dexrazoxane (cardiac
toxicity)
2000s: • AIs (adjuvant) • Fulvestrant • Docetaxel (adjuvant) • Paclitaxel (adjuvant) • N-ab paclitaxel • Ixabepilone • Trastuzumab (adjuvant) • Lapatinib • Bevacizumab • Eribulin • Denosumab
Mostly chemotherapy Mostly stage IV
Adjuvant (early) treatment Chemotherapy, endocrine, targeted Rx
Food and Drug Administration (FDA). Prescription Drug Product List. Available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM071436.pdf. Accessed October 2, 2011
1980s: • Mitoxantrone
Variable Response to Chemotherapy
Regimen
Subtype
T-FAC1
(N=82)
AC-T2
(n=107)
Luminal A/B 2/30 (7%) 4/62 (7%)
Normal-like 0/10 (0) NA
HER2+/ER- 9/20 (45%) 4/11 (36%)
Basal-like 10/22 (45%) 9/34 (26%)
P<0.001 1 Rouzier et al, Clin Cancer Res 2005; 2 Carey LA et al, SABCS 2004
P=0.003
BRCA1 Tumors Are More Sensitive to Anthracyclines Than Sporadic Triple Negatives
BRCA1 Mutated FEC Regimen (n = 19)
Controls FEC Regimen (n = 73)
Median age, years 37 (25-48) 49 (29-66)
Median T, mm 55 (32-90) 50 (30-120)
ER negative, % 84 100
Grade 3, % 83 86
Median NBR cycles 4 (3-6) 4 (3-6)
PCR rate, %* 47 22
pN+, % 16 40
Delaloge S, et al. ASCO 2008.Abstract 574.
*P = .03
Chemotherapy Duration Matters: Progression-Free Survival
Coates 1987 13 0.56 0.44-0.71
Harris 1990 2 1.18 0.65-2.15
Muss 1991 3 0.26 0.16-0.43
Ejlertsen 1993 28 0.71 0.61-0.83
Gregory 1997 10 0.70 0.53-0.92
Falkson 1998 5 0.46 0.31-0.68
Bastit 2000 11 0.65 0.50-0.84
Nooij 2003 8 0.67 0.50-0.90
Gennari 2006 6 1.01 0.71-1.43
Majordomo 2009 8 0.77 0.57-1.05
Alba 2010 6 0.53 0.37-0.76
Overall 100 0.66 0.60-0.72
0.10 1.00 10.00
Test for heterogeneity, P = .001 Test for treatment effect, P < .001
Study Longer Better Shorter Better % Weight HR 95%CI
0.64 0.55-0.76
Gennari A, et al. J Clin Oncol. 2011;29:2144-2149.
Sequential or Combination Therapy for Advanced Breast Cancer?
ECOG 1193: First-line Chemotherapy for Advanced Breast Cancer: Monotherapy vs Combination Therapy
•
Response rates: A = 36%, T = 34%, AT = 47%
Sledge GW, et al. J Clin Oncol. 2003;21:588-592.
Advantages of Combination (Chemo)Therapy • Higher response rate/longer TTP for initial choice of
regimen
• Better for visceral crisis?
Advantages of Monotherapy • You know what is working (or not)
• There is less toxicity
• You know what is causing toxicity
• You can adjust dose in a rational fashion
• Costs are less
• No apparent compromise on survival
Insulin and Breast Cancer Prognosis
0
0.5
1
1.5
2
2.5
3
3.5
< 27 27-35.3 35.3-51.9 > 51.9
HR
Insulin Quartiles (pmol/L)
Death p=0.001
Distant Recurrence
p=0.007
Goodwin PJ et al. J Clin Oncol 2002;20:42-51
Molecular Action of Insulin
Adapted from Vigneri P et al., Endocr Relat Cancer 2009 Jul 20 (epub ahead of print)
NCIC CTG MA.32 STUDY SCHEMA
Metformin 850 mg po bid X 5 years (includes 4-week ramp-up of 850mg po daily)
Placebo One caplet po bid X 5 years (includes 4 week ramp-up of one caplet po daily)
R A N D O M I Z E
T1–3*, N0-3,M0 invasive breast cancer
surgically removed within 1 year Radiotherapy,
chemotherapy**,
endocrine therapy, trastuzumab, biologics,
bisphosphonates
* If pT1C, ≥ 1 adverse prognostic factor
** CXT must be completed
Primary Outcome: Invasive cancer free survival
Secondary Outcome: Overall survival, Distant Disease-Free Survival, Breast Cancer Free Interval,
Adverse Events, Hospitalization (CV, diabetes), QOL (888 subjects)
Embedded Correlative: Weight, Fasting Insulin (baseline, 6 months, 5 years), Tumor Blocks
Sample Size: 3,582 (431 events) – 5 year IDFS 0.85 (placebo), HR =0.76, α=0.05 β=0.20
2 interim analyses (benefit, futility) at 144 and 288 events
Planned subset analyses (α=0.10, 2 sided; β=0.80) in ER/PgR neg (HR 0.65)
and Triple negative (HR 0.55)
Targeting a Weakness in Tumor DNA Repair
Synthetic Lethality
Mutation of either gene alone is compatible with viability, but mutation in both leads to death
Ashworth A. J Clin Oncol 28(22):3785-3790, 2008
PARP Inhibitor Mechanism of Action
BRCA1 BRCA2
1. PLATINUM CHEMOTHERAPY
Inflicts DNA damage via adducts and DNA crosslinking
2. PARP1 UPREGULATION
Base-excision repair of DNA damage
3. INHIBITION OF PARP1
Disables DNA base-excision repair
4. REPLICATION FORK COLLAPSE
Double strand DNA break
CELL SURVIVAL CELL DEATH
PARP1
PARP1
BSI-201
PARP1
Farmer H, et al. Nature. 2005;434:917-920. Personal communication, Alan Ashworth
BRCA1 and BRCA2 -/- Cells Are Very Sensitive to PARP Inhibition
BRCA2 +/-
BRCA2 -/-
Wild type
Log surviving fraction
0 - 4
- 3
- 2
- 1
0
PARP Inhibitor Concentration (M) 10-9 10-8 10-7 10-6 10-5 10-4
Control + PARP inhibitor
Control + PARP inhibitor
Wild type
BRCA2 -/-
Increased levels of chromosomal aberrations in PARP inhibitor–treated BRCA2 -/- cells
OS
GC
(n = 258)
GCI
(n = 261) HR P Value
Median
OS 11.1 mos 11.8 mos 0.88 .28
O’Shaughnessy J, et al. ASCO 2011.Abstract 1007.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12 14 16
Pro
bab
ility
of
Surv
ival
Months
Prespecified alpha = 0.04
Phase III Study of Iniparib in Combination With
Gemcitabine/Carboplatin in Metastatic TNBC: OS – ITT
• 54 patients with BRCA1/2 advanced breast cancer
• Refractory to chemotherapy
• 26 patients with evaluable disease
- ORR: 38% (9/24)
- 1 complete response
Phase II Study: Oral Olaparib, PARP1 Inhibitor in BRCA-Deficient Advanced Breast Cancer
Tutt A, et al. ASCO 2009. Abstract CRA501.
The Genomic Era
2001 2011
The $1000 Genome is Almost Here
Basal-like subtype 1. ~75% of Triple-Negative
Breast Cancers (i.e. tumors
lacking ER, PgR, and HER2)
Keratin 5/6
Luminal A
Normal Breast Basal-like Luminal B
Claudin-low HER2-enriched
Triple Negative: 6 Subtypes and Counting
Lehmann, BD et al. J Clin Invest 121: 2750-67, 2011
TNBC: Genomic Chaos
Shah, S et al. Nature 2012
Oncology as Whack-a-Mole
Rapid emergence of compensatory mechanisms of resistance
Multi-platform PIK3CA Pathway Analysis (390 tumors)
TCGA et al., Nature 2012 (PMID 23000897)
Luminal A Luminal B HER2E Basal-like
39
Thank You